RESUMO
Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti-GluR1 and anti-Gabra1 ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti-Gabra1 ASOs also reduced binding of the GABAA receptor PET ligand 18F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs.
Assuntos
Encéfalo/metabolismo , Antagonistas de Receptores de GABA-A/farmacocinética , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos Antissenso/farmacocinética , Animais , Artérias/diagnóstico por imagem , Artérias/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Flumazenil/administração & dosagem , Flumazenil/análogos & derivados , Antagonistas de Receptores de GABA-A/administração & dosagem , Técnicas de Silenciamento de Genes , Humanos , Injeções Espinhais , Microscopia Intravital , Masculino , Terapia de Alvo Molecular/métodos , Neuroglia/metabolismo , Neurônios/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Pia-Máter/diagnóstico por imagem , Pia-Máter/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Receptores de AMPA/análise , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/genética , Receptores de GABA-A/análise , Receptores de GABA-A/genética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Análise Espaço-Temporal , Tionucleotídeos/administração & dosagem , Tionucleotídeos/farmacocinética , Distribuição TecidualRESUMO
Molecular imaging has been widely applied in preclinical research. Among these new molecular imaging modalities, microPET imaging can be utilized as a very powerful tool that can obtain the measurements of multiple biological processes in various organs repeatedly in a same subject. This review discusses how this new approach provides noninvasive biomarker for neurotoxicology research and summarizes microPET findings with multiple radiotracers on the variety of neurotoxicity induced by toxic agents in both the rodent and the nonhuman primate brain.
Assuntos
Poluentes Ambientais/toxicidade , Sistema Nervoso/efeitos dos fármacos , Animais , Biomarcadores , Encéfalo , Imagem Molecular , Síndromes NeurotóxicasRESUMO
The aim of this study was to determine the uptake of intravenously administered N-[11CH3]-dimethylaminoparthenolide (DMAPT) into orthotopic 9LSF glioblastoma brain tumors in Fisher 344 rats from positron emission tomography (PET) imaging studies. [11C]methyl iodide (11CH3I) was utilized as a [11C]-labeling reagent to label the precursor methylaminoparthenolide (MAPT) intermediate. From PET imaging studies it was found that brain uptake of N-[11CH3]DMAPT into brain tumor tissue was rapid (30min), and considerably higher than that in the normal brain tissue.
Assuntos
Glioblastoma/diagnóstico por imagem , Sesquiterpenos/farmacocinética , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Ratos , Ratos Endogâmicos F344 , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Animals exposed to sevoflurane during development sustain neuronal cell death in their developing brains. In vivo micro-positron emission tomography (PET)/computed tomography imaging has been utilized as a minimally invasive method to detect anesthetic-induced neuronal adverse effects in animal studies. METHODS: Neonatal rhesus monkeys (postnatal day 5 or 6, 3 to 6 per group) were exposed for 8 h to 2.5% sevoflurane with or without acetyl-L-carnitine (ALC). Control monkeys were exposed to room air with or without ALC. Physiologic status was monitored throughout exposures. Depth of anesthesia was monitored using quantitative electroencephalography. After the exposure, microPET/computed tomography scans using F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA) were performed repeatedly on day 1, 1 and 3 weeks, and 2 and 6 months after exposure. RESULTS: Critical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [F]-FEPPA in the frontal and temporal lobes was increased significantly 1 day or 1 week after exposure, respectively. Analyses of microPET images recorded 1 day after exposure showed that sevoflurane exposure increased [F]-FEPPA uptake in the frontal lobe from 0.927 ± 0.04 to 1.146 ± 0.04, and in the temporal lobe from 0.859 ± 0.05 to 1.046 ± 0.04 (mean ± SE, P < 0.05). Coadministration of ALC effectively blocked the increase in FEPPA uptake. Sevoflurane-induced adverse effects were confirmed by histopathologic evidence as well. CONCLUSIONS: Sevoflurane-induced general anesthesia during development increases glial activation, which may serve as a surrogate for neurotoxicity in the nonhuman primate brain. ALC is a potential protective agent against some of the adverse effects associated with such exposures.
Assuntos
Anestésicos Inalatórios/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico por imagem , Éteres Metílicos/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Anestesia Geral , Anilidas , Animais , Animais Recém-Nascidos , Eletroencefalografia/efeitos dos fármacos , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Processamento de Imagem Assistida por Computador , Macaca mulatta , Masculino , Piridinas , Compostos Radiofarmacêuticos , Sevoflurano , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Neural progenitor cell expansion is critical for normal brain development and an appropriate response to injury. During the brain growth spurt, exposures to general anesthetics, which either block the N-methyl-d-aspartate receptor or enhance the γ-aminobutyric acid receptor type A can disturb neuronal transduction. This effect can be detrimental to brain development. Until now, the effects of anesthetic exposure on neural progenitor cell expansion in vivo had seldom been reported. Here, minimally invasive micro positron emission tomography (microPET) coupled with 3'-deoxy-3' [(18)F] fluoro-l-thymidine ([(18)F]FLT) was utilized to assess the effects of sevoflurane exposure on neural progenitor cell proliferation. FLT, a thymidine analog, is taken up by proliferating cells and phosphorylated in the cytoplasm, leading to its intracellular trapping. Intracellular retention of [(18)F]FLT, thus, represents an observable in vivo marker of cell proliferation. Here, postnatal day 7 rats (n = 11/group) were exposed to 2.5% sevoflurane or room air for 9 h. For up to 2 weeks following the exposure, standard uptake values (SUVs) for [(18)F]-FLT in the hippocampal formation were significantly attenuated in the sevoflurane-exposed rats (p < 0.0001), suggesting decreased uptake and retention of [(18)F]FLT (decreased proliferation) in these regions. Four weeks following exposure, SUVs for [(18)F]FLT were comparable in the sevoflurane-exposed rats and in controls. Co-administration of 7-nitroindazole (30 mg/kg, n = 5), a selective inhibitor of neuronal nitric oxide synthase, significantly attenuated the SUVs for [(18)F]FLT in both the air-exposed (p = 0.00006) and sevoflurane-exposed rats (p = 0.0427) in the first week following the exposure. These findings suggested that microPET in couple with [(18)F]FLT as cell proliferation marker could be used as a non-invasive modality to monitor the sevoflurane-induced inhibition of neural progenitor cell proliferation in vivo.
RESUMO
The present study reports on a new strategy for selective, radiation therapy-amplified drug delivery using an antiangiogenic 33-a.a., tumor vasculature-targeting ligand, anginex, to improve the therapeutic ratio for strategies developed against solid tumors. Our findings indicate that galectin-1 is (a) one of the major receptors for anginex (b) overexpressed by tumor neovasculature and (c) further specifically upregulated in endothelial cells in response to radiation exposure as low as 0.5 Gy. An investigation of [18]-F-labeled anginex biodistribution in SCK tumors indicates that anginex is an effective targeting molecule for image and radiation-guided therapy of solid tumors. An anginex-conjugated liposome capable of being loaded with drug was shown to selectively target endothelial cells post-radiation. The presence of endothelial cells in a three-dimensional co-culture system with tumor cells developed to study tumor/endothelial cell interactions in vitro led to higher levels of galectin-1 and showed a further increase in expression upon radiation exposure when compared to tumor cell spheroids alone. Similar increase in galectin-1 was observed in tumor tissue originating from the tumor-endothelial cell spheroids in vivo and radiation exposure further induced galectin-1 in these tumors. The overall results suggest feasibility of using a clinical or subclinical radiation dose to increase expression of the galectin-1 receptor on the tumor microvasculature to promote delivery of therapeutics via the anginex peptide. This approach may reduce systemic toxicity, overcome drug resistance, and improve the therapeutic efficacy of conventional chemo/radiation strategies.
Assuntos
Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Galectina 1/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Lipossomos , Camundongos , Neoplasias/irrigação sanguínea , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/radioterapia , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Ligação Proteica , Esferoides Celulares , Células Tumorais CultivadasAssuntos
Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos/normas , Composição de Medicamentos/normas , Drogas em Investigação/normas , Humanos , Legislação de Medicamentos , Farmacopeias como Assunto , Tomografia por Emissão de Pósitrons/tendências , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
The effects of ionizing radiation, with or without the anti-angiogenic agent anginex (Ax), on multiple myeloma growth were tested in a SCID-rab mouse model. Mice carrying human multiple myeloma cell-containing pre-implanted bone grafts were treated weekly with various regimens for 8 weeks. Rapid multiple myeloma growth, assessed by bioluminescence intensity (IVIS), human lambda Ig light chain level in serum (ELISA), and the volume of bone grafts (caliper), was observed in untreated mice. Tumor burden in mice receiving combined therapy was reduced to 59% (by caliper), 43% (by ELISA), and 2% (by IVIS) of baseline values after 8 weeks of treatment. Ax or radiation alone slowed but did not stop tumor growth. Four weeks after the withdrawal of the treatments, tumor burden remained minimal in mice given Ax + radiation but increased noticeably in the other three groups. Multiple myeloma suppression by Ax + radiation was accompanied by a marked decrease in the number and activity of osteoclasts in bone grafts assessed by histology. Bone graft integrity was preserved by Ax + radiation but was lost in the other three groups, as assessed by microCT imaging and radiography. These results suggest that radiotherapy, when primed by anti-angiogenic agents, may be a potent therapy for focal multiple myeloma.
Assuntos
Inibidores da Angiogênese/farmacologia , Osso e Ossos/cirurgia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/radioterapia , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Transplante Ósseo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Terapia Combinada , Humanos , Camundongos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/cirurgia , Peptídeos , Transporte Proteico , Proteínas/metabolismo , Proteínas/farmacologia , Proteínas/uso terapêutico , Coelhos , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiaçãoRESUMO
RATIONALE: Variation in the rate at which drugs reach the brain influences many different drug effects and is also thought to influence liability to addiction. For example, rapid intravenous delivery of cocaine and nicotine is more effective in producing hedonic effects, tolerance, psychomotor sensitization, and in inducing gene expression. Smoking is thought to result in an especially rapid rate of rise of nicotine in the brain, but whether this is true has never been adequately addressed. Thus, in this study, we sought to determine the true rate of rise of smoked nicotine in human brain and compare this with previous intravenous nicotine delivery. METHODS: Positron emission tomography scans of lung and brain regions and arterial and venous blood curves were obtained in human subjects after single puffs from cigarettes formulated with [(11)C]nicotine. RESULTS: The rise of nicotine concentration following a single puff was rapid, reaching more than 50% of maximum brain levels within 15 s of bolus arrival in the brain in most subjects. This rate of rise was considerably faster than that seen in previous studies using intravenous administration. CONCLUSIONS: Uptake in human brain from a single inhalation was sufficiently rapid that it is plausible that fast rate-of-rise contributes to nicotine dependence in smokers.
Assuntos
Encéfalo/metabolismo , Nicotina/farmacocinética , Agonistas Nicotínicos/farmacocinética , Fumar/metabolismo , Tabagismo/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Feminino , Humanos , Exposição por Inalação , Pulmão/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Nicotina/sangue , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/sangue , Tomografia por Emissão de Pósitrons , Fumar/efeitos adversos , Adulto JovemAssuntos
Aminoácidos/administração & dosagem , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Iofetamina/química , Iofetamina/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Haplorrinos , Aumento da Imagem/métodos , Infusões Intra-Arteriais , Cinética , Ligação Proteica/efeitos dos fármacos , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
It has been reported that suppression of N-methyl-D-aspartate (NMDA) receptor function by ketamine may trigger apoptosis of neurons when given repeatedly during the brain growth spurt period. Because microPET scans can provide in vivo molecular imaging at sufficient resolution, it has been proposed as a minimally invasive method for detecting apoptosis using the tracer (18)F-labeled annexin V. In this study, the effect of ketamine on the metabolism and integrity of the rat brain were evaluated by investigating the uptake and retention of (18)F-fluorodeoxyglucose (FDG) and (18)F-annexin V using microPET imaging. On postnatal day (PND) 7, rat pups in the experimental group were exposed to six injections of ketamine (20 mg/kg at 2-h intervals) and control rat pups received six injections of saline. On PND 35, 37 MBq (1 mCi) of (18)F-FDG or (18)F-annexin V was injected into the tail vein of treated and control rats, and static microPET images were obtained over 1 (FDG) and 2 h (annexin V) following the injection. No significant difference was found in (18)F-FDG uptake in the regions of interest (ROIs) in the brains of ketamine-treated rats compared with saline-treated controls. The uptake of (18)F-annexin V, however, was significantly increased in the ROI of ketamine-treated rats. Additionally, the duration of annexin V tracer washout was prolonged in the ketamine-treated animals. These results demonstrate that microPET imaging is capable of distinguishing differences in retention of (18)F-annexin V in different brain regions and suggests that this approach may provide a minimally invasive biomarker of neuronal apoptosis in rats.
Assuntos
Anestésicos Dissociativos/toxicidade , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Radioisótopos de Flúor/metabolismo , Ketamina/toxicidade , Neurônios/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Animais , Western Blotting , Feminino , Masculino , Neurônios/citologia , Ratos , Ratos Sprague-DawleyRESUMO
Glucose transport rates are estimated noninvasively in physiological and pathological states by kinetic imaging using PET. The glucose analog most often used is (18)F-labeled 2FDG. Compared with glucose, 2FDG is poorly transported by intestine and kidney. We examined the possible use of 6FDG as a tracer of glucose transport. Lacking a hydroxyl at its 6th position, 6FDG cannot be phosphorylated as 2FDG is. Prior studies have shown that 6FDG competes with glucose for transport in yeast and is actively transported by intestine. Its uptake by muscle has been reported to be unresponsive to insulin, but that study is suspect. We found that insulin stimulated 6FDG uptake 1.6-fold in 3T3-L1 adipocytes and azide stimulated the uptake 3.7-fold in Clone 9 cells. Stimulations of the uptake of 3OMG, commonly used in transport assays, were similar, and the uptakes were inhibited by cyclochalasin B. Glucose transport is by GLUT1 and GLUT4 transporters in 3T3-L1 adipocyte and by the GLUT1 transporter in Clone 9 cells. Cytochalasin B inhibits those transporters. Rats were also imaged in vivo by PET using 6(18)FDG. There was no excretion of (18)F into the urinary bladder unless phlorizin, an inhibitor of active renal transport, was also injected. (18)F activity in brain, liver, and heart over the time of scanning reached a constant level, in keeping with the 6FDG being distributed in body water. In contrast, (18)F from 2(18)FDG was excreted in relatively large amounts into the bladder, and (18)F activity rose with time in heart and brain in accord with accumulation of 2(18)FDG-6-P in those organs. We conclude that 6FDG is actively transported by kidney as well as intestine and is insulin responsive. In trace quantity, it appears to be distributed in body water unchanged. These results provide support for its use as a valid tracer of glucose transport.
Assuntos
Desoxiglucose/análogos & derivados , Glucose/metabolismo , Imagem Corporal Total/métodos , Células 3T3-L1 , Animais , Transporte Biológico , Células Cultivadas , Desoxiglucose/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Masculino , Camundongos , Traçadores Radioativos , Ratos , Ratos Sprague-Dawley , Trítio/farmacocinéticaRESUMO
beta-Adrenergic receptor (beta-AR) concentration can be measured in vivo using positron emission tomography (PET) and the high-affinity antagonist [18F]-(S)-fluorocarazolol {[18F]-(S)-FCZ}. However, the influence of endogenous catecholamines on the in vivo binding properties of [18F]-(S)-FCZ should be measured to aid in selection of the model used to estimate receptor concentration based on PET data. Herein we addressed the questions "What is the influence of endogenous catecholamines on the [18F]-(S)-FCZ binding in the heart?" and "In what range are the in vivo concentrations of endogenous beta-AR ligands?" In PET studies, 3 drug regimens were used to manipulate the levels of endogenous catecholamines. The time courses of myocardial concentration of [18F]-(S)-FCZ were compared before and after drug administration. In vitro binding assays and computer simulations were performed to complement the in vivo studies. Despite the large changes of endogenous catecholamines, no significant changes were observed in the [18F]-(S)-FCZ myocardial concentration. In vitro assays showed that (S)-FCZ has an affinity for beta-receptors that is 3900 and 9500 times higher than those of norepinephrine (NE) and epinephrine (EPI), respectively. Computer simulations support the hypothesis that the binding affinities relative to ligand concentrations in vivo are sufficient to explain the apparent lack of effect of endogenous catecholamines on [18F]-(S)-FCZ myocardial concentration. Increased levels of catecholamines in the physiological range do not affect the myocardial concentration of [18F]-(S)-FCZ as measured by PET. This lack of effect suggests that the myocardial concentration of NE at the synaptic sites cannot be higher than 300 nM.
Assuntos
Carbazóis/metabolismo , Catecolaminas/metabolismo , Miocárdio/metabolismo , Tomografia por Emissão de Pósitrons , Propanolaminas/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Ligação Competitiva , Carbazóis/administração & dosagem , Feminino , Radioisótopos de Flúor , Ligantes , Masculino , Propanolaminas/administração & dosagem , SuínosRESUMO
Large volume low-pressure targets were designed for use on the wide-beam Scanditronix MC-17 cyclotron. The design was optimized experimentally by construction of aluminum test targets. Final production targets were constructed of titanium and niobium. The targets tripled the routine production yield of the previous target, giving up to 90 GBq (2.5 Ci) of fluoride and essentially eliminated the need for periodic target maintenance. The final targets represent a considerable improvement. However, they have not performed as well as predicted, indicating that further improvement is possible.
RESUMO
UNLABELLED: There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. METHODS: The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. RESULTS: Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in Tg mice without intranasal injection of the ligands. bFGF and SAP stained neurons around the rim of Abeta deposits and throughout the cortex in Tg mice. There was only weak staining of neurons in Tg mice without intranasal injection of bFGF and no staining of SAP in Tg mice without intranasal injection of SAP. No bFGF or SAP staining was evident in wild-type control mice. CONCLUSION: We report a novel noninvasive method for labeling Abeta plaques. This method may be modified for human studies using intranasal injection of radiolabeled ligands and imaging with SPECT or PET.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Fator 2 de Crescimento de Fibroblastos , Radioisótopos do Iodo , Componente Amiloide P Sérico , Administração Intranasal , Doença de Alzheimer/diagnóstico por imagem , Animais , Encéfalo/metabolismo , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Cintilografia , Componente Amiloide P Sérico/administração & dosagem , Distribuição TecidualRESUMO
Three-dimensional (3-D) positron emission tomography (PET) imaging of inhaled radiolabeled aerosol in the nasal or pulmonary regions provides an in vivo measurement of drug distribution using the drug itself as the tracer. Repeated or dynamic PET scans over the time after inhalation provides us with further information about the fate of the deposited drug. These quantitative measurements are sufficient to describe the performance of a drug or device and they are obtained in a noninvasive fashion, which cannot be achieved by using any other methods. Using this PET-imaging paradigm, we conducted a sequence of drug studies to evaluate the performance of aerosol drugs and delivery devices; to compare the performance of similar drugs from different manufacturers; to assess the similarity between different formulations and propellants for the same drug; to appraise delivery devices such as spacers and nebulizers, etc. This paper reviews only the imaging and data analysis techniques developed for the above-mentioned studies that include multi-modality image registration, region definition and region-based data analysis, and nonregion-based data analysis. We separated the techniques into nasal and pulmonary studies because of the uniqueness of each group. Specific drugs or devices are not identified and no result about drug performance is given because the imaging and data analysis methodology, which is the focus of this paper, applies to all these studies regardless of the drugs or their delivery devices. The quantitative data are used as the scientific basis for evaluation although we also developed visualization techniques to enhance the results drawn from the data.